Abstract
Purpose
Heart failure with reduced ejection fraction (HFrEF) represents a complex clinical syndrome requiring the timely initiation of disease-modifying therapies. However, the optimal timing for introducing these therapies in the hospital setting remains an area of investigation. This study aims to evaluate whether the early in-hospital initiation of sodium–glucose co-transporter 2 inhibitors (SGLT2i) facilitates the introduction of angiotensin receptor–neprilysin inhibitors (ARNI) during hospitalization and whether this strategy is associated with improved left ventricular systolic function at 6-month follow-up.
Methods
In this prospective, observational, single-centre study, consecutive patients with HFrEF were enrolled and divided into two groups on the basis of the timing of SGLT2i initiation: Group 1 (in-hospital) and Group 2 (post-discharge). The differences in terms of ARNI introduction within hospitalization were evaluated in the two groups. Changes in echocardiographic parameters (left ventricular ejection fraction [LVEF], left ventricular end-diastolic volume [LVEDV], left ventricular end-systolic volume [LVESV], E/e′ ratio) at 6-month follow up have been compared among patients treated with ARNI+SGLT2i and SGLT2i alone.
Results
A total of 285 patients were enrolled, 151 for G1 and 134 for G2. Early in-hospital use of SGLT2i was an independent predictor of ARNI initiation before discharge (odds ratio, OR: 3.31; 95% confidence intervals, CI 1.87–5.84; p < 0.001). Among the 89 patients of G1 who completed 6 months of follow-up, early in-hospital therapy with SGLT2i and ARNI represents an independent significant predictor of LVEF > 10% improvement, compared with those treated with SGLT2i alone (OR: 5.353; 95% CI 1.504–12.070; p < 0.003).
Conclusions
Early in-hospital initiation of SGLT2i in patients with HFrEF is associated with a higher likelihood of in-hospital ARNI introduction and with significant improvements in left ventricular systolic function at 6-month follow-up.
Key Points
| The implementation of GDMT in clinical practice remains suboptimal, often resulting in delayed or incomplete initiation and titration of recommended agents. |
| Early in-hospital initiation of SGLT2i in patients hospitalized for HFrEF appears to be a key facilitator of timely ARNI introduction resulting in the significant improvement of LVEF. |
Introduction
Heart failure (HF) represents a major global public health concern due to its increasing prevalence, substantial morbidity and mortality rates and the significant economic burden it imposes on healthcare systems [1]. It is currently estimated that approximately 64 million individuals worldwide are affected by this condition. With a progressively aging population, the prevalence of HF is expected to rise markedly in the coming decades, further exacerbating its social and economic impact [1].
Heart failure with reduced ejection fraction (HFrEF) is defined as a clinical syndrome characterized by typical symptoms and/or signs resulting from structural and/or functional cardiac abnormalities, confirmed by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion, in the presence of a left ventricular ejection fraction (LVEF) ≤ 40% [2]. Patients with HFrEF experience a poor prognosis, high rates of hospital readmission, reduced quality of life and increased healthcare utilization, underscoring the need for timely and effective therapeutic strategies [3].
The 2021 European Society of Cardiology (ESC) guidelines and their 2023 update [1, 4] advocate for the rapid initiation of guideline-directed medical therapy (GDMT), consisting of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor–neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs) and sodium–glucose co-transporter 2 inhibitors (SGLT2i). These pharmacologic pillars are recommended to reduce mortality, prevent HF-related hospitalizations and improve patients’ functional status and quality of life [1]. Moreover, recent studies have demonstrated that early, concurrent initiation of all four therapies during the vulnerable post-discharge phase significantly lowers the risk of adverse outcomes [5, 6]. However, this strategy has not been uniformly evaluated in earlier landmark trials or widely adopted in routine clinical practice, owing to factors such as physician inertia, healthcare system variability and differences between real-world and trial populations [7].
Despite the compelling evidence supporting a comprehensive pharmacologic approach, the implementation of GDMT in clinical practice remains suboptimal, often resulting in delayed or incomplete initiation and titration of recommended agents [8, 9]. This has prompted growing interest in strategies that may accelerate and facilitate optimal therapy initiation. In this context, the early introduction of SGLT2i has emerged as a potential lever to improve GDMT implementation in patients with HFrEF. Although the STRONG-HF trial [5] demonstrated the benefits of intensive early initiation of foundational therapies, it did not incorporate SGLT2i, leaving an important gap in contemporary therapeutic sequencing.
While SGLT2i have been studied primarily as add-on therapies to existing regimens [10, 11], their early use has been hypothesized to improve patient tolerance and facilitate the initiation of other GDMT components [12]. However, data on their early use in real-world settings remain scarce. Given their favourable safety profile, lack of need for dose titration and multifaceted benefits, there is a compelling rationale to investigate whether early SGLT2i initiation during hospitalization may act as a catalyst for the initiation of other therapies, particularly ARNI, and lead to improved cardiac reverse remodelling and biomarker profiles.
Accordingly, the primary aim of this study is to determine whether early in-hospital initiation of SGLT2i facilitates in-hospital ARNI initiation in patients with HFrEF. Additionally, we aim to assess whether this combined early therapeutic approach is associated with improved left ventricular systolic function at 6-month follow-up, during the vulnerable post-discharge phase.
Methods
The present is an observational, prospective, monocentric study enrolling patients with a diagnosis of HFrEF who have been consecutively admitted to the Cardiology Department and Cardiac Intensive Care Unit of the Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences at Policlinico Umberto I, Sapienza University of Rome. Inclusion criteria were the following: (i) written, signed and dated informed consent; (ii) age above 18 years; (iii) diagnosis of HFrEF according to the current guidelines [1]; (iv) indication to start a comprehensive therapy with the four pillars for HFrEF. Exclusion criteria were the following: (i) any condition limiting life expectancy to less than 1 year; (ii) end-stage kidney failure and/or dialysis; (iii) planned or history of heart transplantation and ventricular assist device (VAD); (iv) pregnant or nursing; (v) non-compliance with the study protocol; (vi) SGLT2i assumption prior to study enrolment.
Patients were divided into two groups on the basis of the timing of SGLT2i initiation:
Group 1 (G1): patients who started SGLT2i therapy during the index hospitalization (early initiation)
Group 2 (G2): patients who did not receive SGLT2i during hospitalization but initiated therapy after discharge (delayed initiation)
The pharmacological strategy aimed at early initiation of disease-modifying therapies for HFrEF. SGLT2i and BB were prioritized during hospitalization [12], followed by ARNI and MRAs introduction according to kidney function and blood pressure stability. The early introduction of SGLT2i, even before the other four pillars, was primarily due to their favourable safety profile and the absence of dose titration requirements [12]. The main reason for the difference regarding SGLT2i initiation timing between the two study groups was attributed to the 2023 guidelines update for HF [4], according to which an upfront and early initiation of SGLT2i and the other pillars have been indicated.
Patients’ follow-up was conducted at the dedicated HF outpatient clinic of the same department.
The following parameters have been collected: (i) clinical parameters (past medical history, physical examination, electrocardiogram, arterial blood pressure, New York Heart Association (NYHA) class and pharmacological therapy); (ii) echocardiographic parameters (ventricular chambers size, systolic and diastolic function, valve disease and severity and tricuspid annular plane systolic excursion [TAPSE]); (iii) laboratory parameters (blood cell count, creatinine, electrolytes, estimated glomerular filtration rate [eGFR] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]).
The primary endpoint of the study was to evaluate whether early in-hospital initiation of SGLT2i facilitates the in-hospital introduction of ARNI, compared with patients who started SGLT2i after discharge.
Within G1, we performed an echocardiographic subanalysis to assess whether the in-hospital introduction of ARNI (in addition to SGLT2i) was associated with improved left ventricular function, compared with patients who initiated SGLT2i without ARNI during hospitalization.
Specifically, for the echocardiographic parameters, we used delta (Δ) values, defined as the difference between the measurements after 6 months of therapy and at baseline (hospital discharge), for the following variables: biplane LVEF assessed through Simpson method, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and the E/e′ ratio, defined as the ratio of E wave transmitralic velocity to the mean e′ velocity of the lateral and septal walls. We considered an increase in LVEF greater than 10% compared with baseline an improvement in systolic function [13].
Data were anonymously collected in a dedicated Microsoft Excel database. The study was conducted according to the Helsinki Declaration. All the patients signed the informed consent to participate in the study. The study protocol was approved by the local Ethical Committee (rif.7068 approved on 8 May 2023).
Statistical Analysis
Continuous variables are expressed as mean ± standard deviation (SD) or as median with interquartile range (IQR), depending on their distribution, which was assessed using the Shapiro–Wilk test. Categorical variables are reported as counts and percentages. Comparisons between the two groups (early versus delayed SGLT2i initiation) were performed using the unpaired Student’s t-test or Mann–Whitney U test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables, as appropriate. Changes in echocardiographic and laboratory parameters between baseline (discharge) and 6-month follow-up were assessed using paired t-tests or Wilcoxon signed-rank tests, depending on data distribution. Multivariate logistic regression analysis was used to identify independent predictors of in-hospital ARNI initiation, including early SGLT2i use and other clinically relevant covariates. A separate multivariate linear regression model was used to evaluate the association between early combined therapy (SGLT2i+ARNI) and 6-month changes of echocardiographic parameters compared with patients who did not start in-hospital combined treatment. For all tests, a p-value < 0.05 was considered statistically significant.
The statistical analysis was performed using SPSS version 27.0 for Mac (IBM Software, Inc., Armonk, NY, USA).
Results
A total of 285 consecutive patients with HFrEF were enrolled between April 2022 and December 2024. The mean age of the study population was 71 ± 12 years, and 212 patients (74%) were male. Ischemic heart disease was the predominant aetiology of HFrEF, affecting 161 patients (56.6%). A history of previous hospitalization for HF was reported in 119 patients (42%). At admission, 171 patients (60%) presented with NYHA class ≥ III, while 114 (40%) were in NYHA class ≤ II. The mean LVEF at admission was 28.5% ± 7.4%. The average TAPSE was 18 ± 4 mm. The mean eGFR at admission was 63 ± 25 mL/min. Baseline clinical characteristics of the population are reported in Table 1. The distribution of HFrEF disease-modifying therapies from admission to discharge, stratified by study groups (early versus delayed SGLT2i initiation), is presented in Table 2 and Fig. 1. According to study groups, 102 (67.5%) patients started ARNI in G1, while 56 (41.8%) patients started ARNI in G2, with a percentage difference of ARNI introduction between the two groups of 25.7% (p = 0.001) (Fig. 2). The median time of SGLT2i initiation was 5 [IQR 3–7] days after hospital admission and 30 [IQR 30–60] days after hospital discharge, for G1 and G2, respectively.
Table 1.
Baseline features of the overall population and the two study groups
| Variables | Overall population (N = 285) | G1 (N = 151) |
G2 (N = 134) |
p-value |
|---|---|---|---|---|
| Age, years (± SD) | 71 (12) | 71.2 (11) | 70.8 (13) | 0.467 |
| Male sex, n (%) | 212 (74.4) | 117 (77.4) | 95 (70.9) | 0.203 |
| BMI, kg/m2 (± SD) | 24.7 (4.7) | 24.2 (4.1) | 25.4 (5.2) | 0.030 |
| Previous HFH, n (%) | 119 (41.8) | 64 (42.3) | 55 (41) | 0.819 |
| Ischemic aetiology, n (%) | 161 (56.5) | 85 (56.3) | 76 (56.7) | 0.942 |
| Non-ischemic aetiology, n (%) | 124 (43.5) | 66 (43.7) | 58 (42.3) | 0.942 |
| HTN, n (%) | 213 (74.7) | 111 (73.5) | 102 (76) | 0.613 |
| Type II diabetes mellitus, n (%) | 90 (31.6) | 49 (32.4) | 41 (30.6) | 0.737 |
| Dyslipidaemia, n (%) | 156 (54.7) | 90 (59.6) | 66 (49.2) | 0.080 |
| Familiar history of CVD, n (%) | 86 (30.2) | 49 (32.4) | 37 (27.6) | 0.374 |
| COPD, n (%) | 65 (22.8) | 32 (21.1) | 33 (24.6) | 0.490 |
| Smoking, n (%) | 123 (43.2) | 65 (43) | 58 (43.3) | 0.968 |
| ICD, n (%) | 67 (23.5) | 40 (26.5) | 27 (20.1) | 0.208 |
| CRT-D, n (%) | 24 (8.4) | 14 (9.3) | 10 (7.4) | 0.583 |
| PMK, n (%) | 39 (13.7) | 23 (15.2) | 16 (12) | 0.420 |
| Systolic blood pressure, mmHg (± SD) | 124 (20) | 122 (21) | 126 (20) | 0.101 |
| Diastolic blood pressure, mmHg (± SD) | 73 (13) | 72 (14) | 74 (13) | 0.214 |
| LVEF, % (± SD) | 28.5 (7.4) | 28.3 (7) | 28.7 (7.6) | 0.655 |
| TAPSE, mm (%) | 18 (4) | 18 (4) | 17.3 (4.1) | 0.159 |
| LVEDD, mm (± SD) | 59.3 (8.6) | 59.7 (8.7) | 59 (8.4) | 0.488 |
| PW, mm (± SD) | 10 (1.6) | 9.5 (1.5) | 9.7 (1.6) | 0.334 |
| IVS, mm (± SD) | 11 (1.9) | 10.5 (1.8) | 10.8 (2) | 0.214 |
| eGFR, mL/min (± SD) | 63 (25) | 64 (24) | 60 (26) | 0.181 |
| Hb, g/dL (± SD) | 12.7 (2.3) | 12.8 (2.3) | 12.6 (2.2) | 0.363 |
| K+, mmol/L (± SD) | 4 (0.3) | 3.9 (0.1) | 4.1 (0.4) | 0.170 |
| Na+, mmol/L (± SD) | 139 (4.6) | 139 (4.7) | 139 (4.5) | 0.383 |
| NYHA class, n (%) | ||||
| I | 10 (3.5) | 6 (4) | 4 (2.9) | 0.654 |
| II | 103 (36.1) | 51 (33.7) | 52 (38.8) | 1 |
| III | 122 (42.8) | 65 (43) | 57 (42.5) | 0.370 |
| IV | 50 (17.5) | 29 (19.2) | 21 (15.7) | 0.161 |
BMI body mass index, COPD chronic obstructive pulmonary disease, CRT-D cardiac resynchronization therapy with defibrillator, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, Hb haemoglobin, HF heart failure, HFH heart failure hospitalization, HTN arterial hypertension, ICD implantable cardioverter defibrillator, IVS interventricular septum, K+ potassium, LVEDD left ventricular end diastolic diameter, LVEF left ventricular ejection fraction, Na+ sodium, NYHA New York Heart Association, PMK pacemaker, PW posterior wall, TAPSE tricuspid annular plane systolic excursion
Table 2.
Distribution of disease-modifying drugs for heart failure and furosemide in overall population, group 1 and 2 (G1 and G2), at hospital admission and discharge
| Drug | Overall population (N = 285) | G1 (N = 151) |
G2 (N = 134) |
p-Value |
|---|---|---|---|---|
| Admission | ||||
| ARNI, n (%) | 36 (12.6) | 12 (7.9) | 24 (17.9) | 0.012 |
| ACEi, n (%) | 63 (22.1) | 32 (21.1) | 31 (23.1) | 0.693 |
| ARBs, n (%) | 34 (12) | 18 (11.9) | 16 (11.9) | 0.996 |
| MRAs, n (%) | 74 (26) | 32 (21.2) | 42 (31.3) | 0.051 |
| BB, n (%) | 184 (64.6) | 101 (66.9) | 83 (61.9) | 0.384 |
| Furosemide, n (%) | 153 (53.7) | 75 (49.7) | 78 (58.2) | 0.149 |
| Discharge | ||||
| ARNI, n (%) | 189 (66.3) | 113 (74.8) | 76 (56.7) | 0.001 |
| ACEi n (%) | 39 (13.7) | 19 (12.6) | 20 (14.9) | 0.566 |
| ARBs, n (%) | 18 (6.3) | 7 (4.6) | 11 (8.2) | 0.216 |
| MRAs, n (%) | 191 (67) | 89 (58.9) | 102 (76.1) | 0.992 |
| BB, n (%) | 267 (93.7) | 141 (93.4) | 126 (94) | 0.821 |
| Furosemide, n (%) | 220 (77.2) | 114 (75.5) | 106 (79.1) | 0.469 |
ACEi angiotensin-converting enzyme inhibitors, ARBs angiotensin receptor blockers, ARNI angiotensin receptor–neprilysin inhibitor, BB beta blockers, MRAs mineralocorticoid receptor antagonists
Fig. 1.
Percentage of patients on therapy with four pillars for HF and furosemide according to admission and discharge. ARNI angiotensin receptor neprilysin inhibitor, BB beta blockers, MRAs mineralcorticoid receptor antagonists, SGLT2i sodium–glucose co-transporter 2 inhibitors
Fig. 2.
Graphical representation of in-hospital ARNI initiation according to study groups. The red column (on ARNI) represents the number of patients who introduced ARNI during hospitalization, while the blue column (off ARNI) represents the number of patients who did not introduce ARNI during hospitalization. The percentage of patients who introduced ARNI according to study groups has been represented. ARNI angiotensin receptor neprilysin inhibitor, SGLT2i sodium–glucose co-transporter 2 inhibitors
Exploratory descriptive analysis regarding the occurrence of main adverse events at 6-month follow up has been included in Table 3.
Table 3.
Exploratory analysis regarding the occurrence of main adverse outcomes in the overall population and both study groups at 6-month follow-up
| Outcomes | Overall population (N = 285) | G1 (N = 151) |
G2 (N = 134) |
p-value |
|---|---|---|---|---|
| CV death | 19 (6.6) | 7 (4.6) | 12 (9) | 0.160 |
| HFH | 19 (6.6) | 11 (7) | 8 (6) | 0.812 |
| All-cause death | 25 (8.7) | 10 (6.6) | 15 (11) | 0.209 |
| WHF | 42 (14.7) | 17 (11) | 15 (11) | 1 |
Worsening heart failure included a composite of urgent ambulatory visits due to symptoms/signs worsening, day-hospital intravenous furosemide administration and increase in oral furosemide
CV cardiovascular, HF heart failure, HFH heart failure hospitalization, WHF worsening heart failure
Univariate analysis showed that LVEF (p = 0.044) and eGFR (p < 0.001) at admission; SGLT2i (p < 0.001), MRAs (p < 0.001) and furosemide (p = 0.014) in-hospital introduction; and MRAs (p = 0.007) and furosemide (p = 0.001) at baseline were significantly associated with in-hospital ARNI introduction. Multivariate analysis instead demonstrated that only the early SGLT2i in hospital introduction (odds ratio, OR: 3.307; 95% confidence intervals, CI 1.872–5.840; p < 0.001) and eGFR at admission (OR: 1.013; 95% CI 1.001–1.026; p = 0.031) were independent predictors of in-hospital ARNI introduction. Univariate and multivariate analysis are presented in Table 4.
Table 4.
Univariate and multivariate analysis regarding the variables influencing the introduction of ARNI during the hospitalization
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p-value | OR | 95% CI | p-value | |
| Gender | 0.767 | 0.446–1.137 | 0.336 | |||
| Age | 0.987 | 0.967–1.006 | 0.181 | |||
| Ischemic aetiology | 0.781 | 0.487–1.254 | 0.307 | |||
| Previous HF hospitalization | 0.891 | 0.555–1.431 | 0.634 | |||
| NYHA class at admission | 1.248 | 0.923–1.687 | 0.150 | |||
| HTN | 0.627 | 0.361–1.087 | 0.097 | 0.616 | 0.312–1.215 | 0.162 |
| LVEF at admission | 0.967 | 0.937–0.999 | 0.044 | 0.969 | 0.933–1.006 | 0.101 |
| TAPSE at admission | 0.998 | 0.943–1.056 | 0.947 | |||
| eGFR at admission | 1.022 | 1.012–1.033 | < 0.001 | 1.013 | 1.001–1.026 | 0.031 |
| SGLT2i in-hospital introduction | 2.899 | 1.788–4.703 | < 0.001 | 3.307 | 1.872–5.840 | < 0.001 |
| MRAs in-hospital introduction | 2.987 | 1.774–5.028 | < 0.001 | 2.409 | 1.014–5.722 | 0.066 |
| BB in-hospital introduction | 1.466 | 0.886–2.426 | 0.136 | |||
| Furosemide in-hospital introduction | 1.927 | 1.144–3.245 | 0.014 | 0.782 | 0.299–2.045 | 0.616 |
| MRAs at baseline | 0.477 | 0.278–0.816 | 0.007 | 1.140 | 0.453–2.868 | 0.781 |
| BB at baseline | 0.644 | 0.392–1.057 | 0.082 | 0.857 | 0.428–1.716 | 0.664 |
| Furosemide at baseline | 0.448 | 0.277–0.724 | 0.001 | 0.697 | 0.275–1.769 | 0.448 |
BB beta blockers, CI confidence interval, eGFR estimated glomerular filtration rate, HF heart failure, HTN arterial hypertension, LVEF left ventricular ejection fraction, MRAs mineralocorticoid receptor antagonists, NYHA New York Heart Association, OR odds ratio, SGLT2i sodium–glucose co-transporter 2 inhibitors, TAPSE tricuspid annular plane systolic excursion
At 6-month follow-up, 18 (16%) and 9 (11.7%) patients reached the target dose of 97/103 mg twice daily (bid) for sacubitril/valsartan for G1 and G2, respectively, and 7 (35%) and 6 (31%) patients reached the target dose of ACEi (ramipril 5 mg bid) for G1 and G2, respectively. In total, 24 (17%) and 19 (15%) patients reached the target dose of BB (10 mg/day for bisoprolol or 25 mg bid for carvedilol) for G1 and G2, respectively, and 47 (53%) and 63 (50%) patients reached the target dose of MRAs (25 mg/day for spironolactone or 50 mg/day for potassium canrenoate) for G1 and G2, respectively. All the patients on SGLT2i were on the maximum dose of 10 mg/day (dapagliflozin or empagliflozin). The median dose of furosemide was 25 mg [IQR 25–75] for both groups at hospital discharge and at the end of 6-month follow-up.
Regarding the main iatrogenic side effects in the total population, 11 (4%) patients showed a significant hyperkalaemia requiring a potassium binder initiation, 14 (5%) patients experienced a urinary infection leading to a temporary SGLT2i interruption and 23 patients (8%) experienced an episode of symptomatic hypotension.
A subgroup analysis on G1 was performed. A total of 89 patients had a complete follow-up at our HF outpatient clinic for a period of 6 months, while the other 24 patients were been included in the analysis owing to missing data. In total, 55 out of 113 patients who were started on SGLT2i+ARNI during hospitalization (S+A group) were compared with 34 patients in the group treated with SGLT2i alone (S group). Baseline echocardiographic parameters and NT-proBNP values are listed in Table 5. We observed a significant change in Δ LVEF (11.4 ± 8 versus 7 ± 7; p = 0.033) with no significant changes in E/e′ ratio (p = 0.075), Δ LVEDV (p = 0.574) and Δ LVESV (p = 0.365), while maintaining comparable background HF therapy. At 6-month follow-up, 42 patients in the S+A group compared with 16 patients in the S group (p = 0.006) had an increase in LVEF greater than 10% compared with their baseline. Echocardiographic measurements are represented in Table 6. Multivariate analysis showed that the presence of ARNI on top of SGLT2i was associated with a significantly increased likelihood of the event (occurrence of LVEF improvement > 10% from baseline to 6 months of follow-up), indicating 5.3-fold higher odds compared with those not assuming ARNI+SGLT2i (OR: 5.353; 95% CI 1.504–12.070; p < 0.003). The multivariate analysis is presented in Table 7.
Table 5.
Subanalysis within G1 group: baseline echocardiographic parameters and NT-proBNP of the S + A group (SGLT2i + ARNI) versus the S group (SGLT2i only)
| Variables | Overall population (N = 89) |
S+A (N = 55) |
S (N = 34) |
p-value |
|---|---|---|---|---|
| LVEF, % (± SD) | 28 (8) | 29 (8) | 26 (8) | 0.089 |
| E/e′ ratio (± SD) | 12 (5) | 12 (5) | 14 (6) | 0.093 |
| LVEDV, mL (± SD) | 161 (73) | 161 (81) | 160 (51) | 0.948 |
| LVESV, mL (± SD) | 115 (61) | 115 (67) | 116 (38) | 0.936 |
| NT-proBNP, pg/mL [IQR] | 936 [448–1838] | 835 [462–2098] | 1596 [798–4106] | 0.192 |
E/e′ ratio between E wave trans mitral velocity and the mean of e′ velocity of lateral and septal walls measured with tissue Doppler, IQR interquartile range, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, LVESV left ventricular end-systolic volume, NT proBNP N-terminal pro b-type natriuretic peptide, SD standard deviation,
Table 6.
Analysis of echocardiographic and NT-proBNP parameters between baseline and 6-month follow-up between the S + A group (SGLT2i + ARNI) and the S Group (SGLT2i only)
| LV parameters | S+ A (N = 55) |
S (N = 34) |
p-value |
|---|---|---|---|
| Δ LVEF, % (± SD) | 11.4 (8) | 7 (7) | 0.033 |
| Δ E/e′ ratio (± SD) | − 4 (5) | − 1 (6) | 0.075 |
| Δ LVEDV, mL (± SD) | − 27 (30) | − 23 (20) | 0.574 |
| Δ LVESV, mL (± SD) | − 26 (24) | − 21 (21) | 0.365 |
| LVEF > 10%, n (%) | 42 (77) | 16 (48) | 0.006 |
E/e′ ratio between E wave trans mitral velocity and the mean of e′ velocity of lateral and septal walls measured with tissue Doppler, LV left ventricular, LVEDV left ventricular end-diastolic volume, LVESV left ventricular end-systolic volume, LVEF left ventricular ejection fraction, Δ differences of values between 6-month follow-up and discharge from hospital
Table 7.
Multivariate analysis for LVEF > 10% from baseline to 6 months after therapy
| Variables | OR | 95% CI | p-value |
|---|---|---|---|
| Male gender | 0.863 | 0.302–2.501 | 0.800 |
| Age | 1.010 | 0.970–1.052 | 0.247 |
| BSA | 0.630 | 0.226–1.746 | 0.213 |
| HTN | 1.262 | 0.421–3.751 | 0.790 |
| Dyslipidaemia | 0.748 | 0.748–2.263 | 0.393 |
| Type II diabetes mellitus | 1.430 | 0.469–4.313 | 0.463 |
| Atrial fibrillation | 1.680 | 0.498–5.703 | 0.331 |
| ARNI in-hospital introduction | 5.353 | 1.504–12.070 | 0.003 |
| NT-proBNP at baseline | 1.121 | 0.768–3.987 | 0.578 |
| NYHA at baseline | 1.679 | 0.533–5.397 | 0.085 |
ARNI angiotensin receptor–neprilysin inhibitor, BSA body surface area, CI confidence interval, HTN arterial hypertension, NT-proBNP N-terminal pro-brain natriuretic peptide, OR odds ratio
Discussion
Despite continuous progress in both pharmacological and non-pharmacological approaches to HF, this complex clinical syndrome remains a major challenge for healthcare systems owing to its persistent morbidity, mortality and socio-economic burden. The ESC guidelines provide clear and updated recommendations on the pharmacological management of HF, with the 2023 update emphasizing the importance of achieving GDMT within a short time frame [1, 4].
The early post-discharge period represents a vulnerable phase, during which rates of hospital readmission and death exceed 25% [14]. In this context, the rapid up-titration of GDMT has proven to be a key prognostic factor. The STRONG-HF trial [5] was pivotal in demonstrating that early and intensive GDMT, with ≥ 50% of target doses reached within 90 days, was safe and significantly reduced cardiovascular (CV) death and HF readmissions, while improving symptoms and quality of life. However, limitations to its applicability include the exclusion of SGLT2i from the GDMT protocol and incomplete up-titration of the other drug classes [5]. According to current ESC recommendations [1, 4], the pharmacological management of HFrEF is based on LVEF and clinical status, endorsing the initiation of the four fundamental therapies as class I indications. Nevertheless, these criteria do not always accurately reflect the underlying haemodynamic status or pathophysiological processes, particularly in acute care settings. Furthermore, gaps remain regarding the optimal sequencing and timing of GDMT initiation, especially in the chronic phase of HF [15]. Evidence addressing these clinical gaps is still limited.
The TITRATE-HF registry [16], a recently published prospective study encompassing the full LVEF spectrum, investigates guideline adherence, barriers to GDMT implementation and long-term outcomes. Among treatment of patients with HFrEF, BB and ACEi/ARNI were most frequently initiated first, followed by MRAs and SGLT2i. The simultaneous introduction of all four drug classes occurred in only 7.8% of patients. At the time of diagnosis, ACEi/ARNI were prescribed in 41.9% of patients, BB in 33%, MRAs in 29.4% and SGLT2i in just 15.7%. These findings highlight a heterogeneous therapeutic approach and underline existing implementation gaps in real-world practice [1, 4, 17]. Despite guideline recommendations [1, 2, 4], the four pillars of HF therapy remain widely underutilized, and further research is needed to optimize their implementation [18]. In this context, SGLT2i are emerging as a rational first-line option in the hospital setting, owing to their early benefits and favourable tolerability profile [19, 20].
In this context, our study provides novel insights by demonstrating that early in-hospital initiation of SGLT2i is an independent predictor of in-hospital ARNI initiation (p < 0.001) together with eGFR values at hospital admission (p = 0.031). Although major clinical events were collected during follow-up, no statistically significant differences were observed between the study groups. At echocardiographic subgroup analysis, patients receiving both SGLT2i and ARNI during hospitalization (S+A group) exhibited significantly greater improvements in LVEF (p = 0.003) at 6-month follow-up compared with those who received SGLT2i alone (S group), indicating an additive clinical benefit from early combination therapy.
Mechanistically, SGLT2i exert pleiotropic effects beyond glucose lowering, including osmotic diuresis and natriuresis, which help reduce cardiac preload, afterload and systemic congestion. Although their diuretic action attenuates over time, the preferential reduction of interstitial fluid improves ventricular loading conditions. At the cellular level, SGLT2i improve myocardial energetics by promoting a shift towards ketone body and fatty acid metabolism, enhancing mitochondrial function and inhibiting the myocardial Na⁺/H⁺ exchanger. These mechanisms reduce oxidative stress and inflammation, contributing to favourable cardiac remodelling and improved HF outcomes [21–27]. Carluccio et al. [28] demonstrated that SGLT2i significantly decreased LVEDV and LVESV, promoting reverse cardiac remodelling and improving systolic function. Another meta-analysis [29] reported a significant improvement in cardiac function and structure in patients treated with SGLT2i compared with placebo.
ARNI therapy, by combining neprilysin inhibition with angiotensin receptor blockade, simultaneously increases levels of endogenous natriuretic peptides and blocks the harmful effects of angiotensin II. This dual mechanism results in vasodilation, natriuresis, anti-fibrotic effects and improved myocardial structure and function. In HFrEF, ARNI has demonstrated superiority over ACE inhibitors and ARBs in reducing CV death and HF hospitalization, while also increasing systolic function [30–34]. In a real-world cohort [35], sacubitril/valsartan increased LVEF by an average of 5% (from 25.3% to 30.1%) over a median period of 3 months, with additional improvements observed in left ventricular dimensions and mass.
From a biomarker perspective, both SGLT2i and ARNI are effective in reducing NT-proBNP levels, an established surrogate for myocardial wall stress and a predictor of clinical outcomes. However, the utility of NT-proBNP for therapy guidance remains under discussion [36, 37].
Early SGLT2i initiation provides mechanistic benefits and is user-friendly, as they do not require dose titration, making them ideal candidates for rapid implementation in the acute setting [38]. Conversely, ARNI must be gradually up-titrated through three dosing levels to reach the maximum tolerated dose, often complicating rapid optimization. Therefore, early SGLT2i use may facilitate the more timely and effective initiation of other GDMT components.
By promoting osmotic diuresis with minimal neurohormonal activation, SGLT2i may help achieve a more stable euvolemic state and optimize interstitial fluid balance without causing a significant drop in blood pressure [21–27]. This haemodynamic stability could facilitate the initiation of ARNI, whose blood pressure-lowering effect is more pronounced. Early SGLT2i use may improve renal function and reduce congestion, both of which are known predictors of successful GDMT intensification [21–27].
This concept is supported by a recent network meta-analysis by Yan et al. [39], which found similar efficacy between SGLT2i and ARNI for primary outcomes (hazard ratio, HR: 0.93; 95% CI 0.82–1.06) but showed that combination therapy significantly reduced the risk of HF hospitalization and CV death compared with ARNI monotherapy (HR: 0.68; 95% CI 0.53–0.89). Similarly, Ji et al. [40] confirmed that both ARNI and SGLT2i significantly reduce CV death and HF hospitalization in HFrEF, with ARNI ranking highest in overall efficacy and SGLT2i offering the most favourable renal safety profile. In addition, Mo et al. [41] found that the combination of SGLT2i and ARNI may exert a beneficial and adjunctive effect compared with monotherapy, reducing death and hospitalization rates. Other studies [42, 43] demonstrated that the combination of ARNI and SGLT2i resulted in greater improvements in LVEF and cardiac function parameters than monotherapy with one on the abovementioned drugs.
Taken together, these findings suggest a paradigm shift in HFrEF management: SGLT2i should not be considered solely as adjunctive or delayed therapy but rather as frontline agents that may facilitate broader and earlier GDMT implementation during the vulnerable post-hospitalization phase. This aspect is crucial in the light of a personalised, patient-tailored approach [44–46].
This study has some limitations. Its single-centre and observational design may limit the generalizability of the findings. Although multivariate analysis was used to control for potential confounding factors, the influence of unmeasured variables cannot be entirely excluded. Several data regarding echocardiographic parameters and biomarkers were not available for the subanalysis. While the present analysis focused on surrogate markers of pathophysiological efficacy, future studies evaluating long-term clinical outcomes as the primary outcome, including hard endpoints such as mortality and rehospitalization on a larger population, are needed to further validate our results. A subanalysis including the main hard endpoints according to the achieved dose of HF drugs is missing, and it may represent a future perspective. A comprehensive long-term analysis on HF drug up-titration in the outpatient setting and a comprehensive analysis of safety endpoints may represent a perspective for future studies.
Conclusions
Early in-hospital initiation of SGLT2i in patients hospitalized for HFrEF appears to be a key facilitator of timely ARNI introduction. This early combination therapy is associated with significant improvement of LVEF at 6-month follow-up. These findings support the strategy of early in-hospital implementation of SGLT2i and ARNI as a practical and effective approach to accelerate GDMT during the vulnerable post-discharge phase, potentially translating into improved long-term outcomes.
Funding
Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. This work did not receive external funding.
Declarations
Conflicts of Interest
Andrea D’Amato, Silvia Prosperi, Federico Ferranti, Claudia Cestiè, Vincenzo Myftari, Rosanna Germanò, Camilla Segato, Matteo Aulicino, Stefanie Marek-Iannucci, Giovanna Manzi, Domenico Filomena, Marco Valerio Mariani, Lucia Ilaria Birtolo, Silvia Papa, Massimo Mancone, Viviana Maestrini, Roberto Badagliacca, Carmine Dario Vizza and Paolo Severino declare no conflicts of interest or competing interests.
Ethics Approval
Not applicable.
Consent to Participate
All the authors participated in the study and made significant intellectual contributions to the manuscript.
Consent for Publication
The manuscript is not currently under consideration elsewhere, and the work reported will not be submitted for publication elsewhere until a final decision has been made as to its acceptability by the journal.
Availability of Data and Material
Not applicable.
Code Availability
Not applicable.
Author Contributions
A.D., S.P. and P.S. conceptualized the study; A.D., S.P., F.F., C.C., V.M., R.G., C.S., M.A. and P.S. performed data curation; A.D., S.P., P.S. and M.V.M. conducted the formal analysis and performed the methodology; M.M., V.M., R.B., C.D.V. and P.S. supervised the study and performed validation and visualization; A.D., S.P., F.F., C.C., V.M., R.G., C.S., M.A., S.M.I., G.M., D.F., M.V.M., L.I.B. and S.P. performed writing—original draft and writing—review and editing. All authors have read and agreed to the published version of the manuscript.
Footnotes
Andrea D’Amato and Silvia Prosperi contributed equally.
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